US 3136695 A
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United States Patent 3,136,695 ANHYDROUS THIXOTROPIC GEL SUSTAINED RELEASE THERAPEUTIC COMPOSITIONS AND METHOD OF PREPARATION Robert Paul Tanse y, Hudson, Ohio, assignor to Strong Cobb Amer Inc., Cleveland, Ohio, a corporation of New York No Drawing. Filed Mar. 10, 1961, Ser. No. 94,696 12 Claims. 0. 167-82) This invention relates to novel compositions of matter which are initially formed within a liquid phase and subsequently transformed into a dry, solid phase and more particularly with the incorporation of one or more therapeutically active substances into a homogeneous system which is specially devised to meet predetermined specifications relating to the stability and release of these agents from a prepared matrix. The system can be applied to the preparation of stabilized forms of pharmaceutical products or to the fabrication of sustained release medication. \Vithminor adjustments and modifications, the release of one or more active ingredients from the matrix can be regulated to occur within short or extended periods of time in either acid or alkaline media. 7 Chemical substances characterized as being water-soluble or water-insoluble can be integrated into the proposed system and subsequently processed, using standard procedures into a variety of pharmaceutical forms. Certain liquid materials which are water-soluble, water-miscible or water-immiscible can also be made into solid, dry compositions of matter.
It is an object of this invention-to produce stable forms of therapeutic agents which can be designed to possess definite time release characteristics. A further object is to provide practical, workable and feasible compositions 1 of matter that can be readily prepared by and adapted to standard pharmaceutical processing techniques in'which reproducible results can be consistently obtained.
In accordancewith the invention it has been found that medicinally active substances which are integrated into 'the new system possess enhanced physical and chemical stability. Also, it was found that the treated material are familiar to those in the art of compounding.
With the advent of more complicated medicinal prod- .ucts, with particular reference to time release drugs, a 'number of systems have been recommended to meet the requirements of this form of medication. Some of these systems make use of aqueous menstruums or slugging 1 procedures to obtain uniform powder or granule forms that can be further processed into pharmaceutical products. Others cite physical mixtures of therapeutic agents in wax-like materials whereby the base substance is first melted at elevated temperatures in order to incorporate the active agents by a physical mixing procedure. Other "becomes more fiowable, more compressible and more easily fabricated into desired pharmaceutical products than when the usual standard procedures are'used, which methods describe the use of special coating procedures 3,136,695 Patented June 9, 1964 ice This invention comprises a novel method of integrating one or more therapeutic agents in a matrix using anhydrous media to produce a stable, intact and unified product. The main ingredient of the invention is a specially modified hydroxy glyceryl ester of a monobasic acid consisting of 18 carbon atoms and the ester having anacid value of 2 and known commercially as Thixcin R (Baker Castor Co.). This ester, which can be characterized as being a hydrophobic sol, and which is a modified l-hydroxy stearin and a glycerol partial ester of stearic acid, has the facility of converting an organic system into a semi-rigid mass. It acts as a sol in the solvent phase and is formed into thread-like aggregates which interlock and disperse throughout the liquid. These highly porous semisolid aggregates are capable of adsorbing other substances and a uniform gel like mass can be formed with suitable stirring. Since the glyceryl ester forms a colloidal dispersion in organic solvents at room temperature, it has been found best to operate under'these conditions. Higher levels of heat dissolvethe sol and upon cooling agglomerates of the ester are formed, which are dilficult to disperse. Because of the capability of the glyceryl ester to create a reversible isothermal sol-gel formation with selected anhydrous solvents, this'invention affords a unique means of producing uniform and reproducible pharmaceutical products. More commonly expressed, the
liquid phase containing the hydrophobic sol and other additives is thixotropic, and the gelled mass .becomes freefiowing during agitation, but sets up to a gel again when it remains undisturbed. The application of this phenomenon to powder granulation procedures is unique and once as low molecular-weight alcohols, e.g., lower alkyl alco-' hols such as methyl alcohol, ethyl alcohol and isopropyl alcohol, as well as chloroform, acetone, trichloroethylene, methylene chloride and petroleum ether can be used, and mixtures thereof.
Also, it can be shown that with the judicious selection of certain additives, which can be readily incorporated in the system, much greater flexibility can be imparted to the matrix in terms of controlled drug release and physical and chemical properties of this novel composition of matter. The release of a therapeutic. substance from the prepared matrix is eifected'through'processes of erosion and leaching in aqueous media (i.e., body fluids).
The type of additive to be used can be chosen from several classifications of chemical compounds and'is dependent solely upon whati s desired in the final formulation. Examples of some of the additives which proved to be elfective are certain water-soluble or water insoluble cellulose gums (i.e., carboxy methyl cellulose, methyl cellulose, ethyl cellulose, and hydroxy ethyl cellulose). Some polyvinyl compounds prove advantageous, such as polyvinyl-pyrrolidone, and certain polyvinyl alcohols and acetates.
which can be used are polyethylene glycol esters of stearic acid, sorbitan fatty acid esters, polyoxypropylene compounds and polyethylene glycols. also be used to advantage, depending on the particular product being produced and the properties desired therein thus providing unusual versatility.
Mixtures thereof can. i
This invention also embraces the use of agents which 7 are added specifically to maintain the stability of the one or more therapeutically active agents present ,in a particular matrix. -Substances classified as stabilizers, preservatives, chelating agents and. buffering compounds can be used. More specifically, antioxidants (i.e., butylated hydroxy anisole, butylated hydroxytoluene, no'rdihydroguaiaretic acid, ascorbyl palmitate, mixed tocopherols and ethyl hydrocaffeate) proved' to be effective in stabilizing certain vitamins. The addition of chelating substances in one layer and 8 mg; in the other.
Additional examples are given to illustrate plications of the new matrix system.
Example 11 A two-layer tablet containing 12 mg. "of'chlorpropheni pyridamine maleate was made in which 4 mg. was put processed to contain 4 grams of the chlorprophenpyridamine maleate and 15 grams of the above hydroxy glyceryl ester dispersed in lactose. Layer.#2'was"made up to contain an 8 to 40 ratio. of the activeagent to the hydrophobic sol in lactose. The separate granulations'were made using a mixture of trichloroethylene and ethyl al- '(i.e., calcium chelate of disodium ethylenediaminetetra j acetic acid and citric acid) proved to be satisfactory.
Pharmaceutical forms made in accordance with'this in- .vention and methods for preparation of'these forms (i.e.,
lowing examples. I
Example I Samples of acetylsalicylic acid were prepared using. different amounts of the modified hydroxy glyceryl ester,
respectively, and tablets were made. I
In one Sample grams of acetylsalicylic acid are mixed with 35 grams of lactose and grams of the hy-' .drophobic sol until a uniform blend is produced. 'In
the second sample is a similar blend ismade, but only 5 grams of the hydrophobic sol'is used. I
Both samples are separately granulated with a solvent phase composed of methylene chloride and methyl alcohol. Soft, solvent-wet masses areformed which solidify as the solvent evaporates; ,The'respective gel masses can be screened to ,theproper' granule size either before or Drying is done using sufiicient heat to cause evaporation. If time is not afactor subsequent to the drying cycle.
drying can be done under ordinary room temperature conditions.
' powders, capsules and tablets) are-illustrated in the fol- After the granulations are dry, 20 grams ofdried starch are incorporated in each sample and lastly are added as Iubricants'ZS grams of talcum and 2.5 grams ofSterotex. Samples were made to'contain' 300 mg."of acetylsalicylic acid per tablet.
The release data obtained on the acetylsalicylic acid usingartificial gastric and intestinal andSample 2 are as follows:
percent I After 1 hour gastric fluid 15 25 4O '46 58 61 71 are: 8 hours intestinal fluid.. s2 s9 1 "Tl1e U.S.'P method for determining tablet disintegra- 7 tion was used to get these values. The tablets in both formulations eroded evenly during the testing period. Although Example I specifically refers to acetylsalicylic acid,.it should be understoodthat other medicinally acfluids on Sample 1 I matrix' along with the phenobarbital, hydroxy glyceryl-p to form products having specified release patterns either 1 orin combinations as components of the described system to. roduce time release products. Also,- vitamins can betreated to produce sustained releaseand/or -more stable forms. I
cohol." The gel mass in each case was screened and: dried similarly to'that'described in. Example, 1.1 After; lubricants (i.e., talcum, magnesium stearateyar e blended in the respective granulations, tablets are compressedon a two-layertablet press;v
In order to establish the specific releasepatterns inf each layer additional tablets were made as simplecompressed tablets using a portion, of each layer granulation.
Release data of the chlorprophenpyridamine maleate on therespectivelayer tablets and on'the two layeri'tablet are asfollowsz. I j
Layer 1 tame-4 mg. 01mm agent; Layer 2 (tablet) 8 mg. of active agent. Two-layer tablet-r12 mg. of active agent. V
"Em l? 11.
-modified hydroxy glyceryl ester, iexceptthat in one of the samples a hydrophiliiccelldlo'se gum was addedto modify the'release pattern I The ingredients arid -their amounts areas'followsz The methyl-cellulose infrabnr #2 is integrated in the that described, in the previous examples. V
The release data obtained on phenobarbital lated body fluids in the U.S..P,. tablet disintegration apester, and lactose. Eachgranulation-is made similarly to paratus'is as follows: N g tive compounds can also be incorporated inthe system p 7 Cumulatiyerei 1- ea -p cent further ap- I Layer #1 was J Two separate tablet samples containing phenobarbital were made usingjthe'same ratios of phenobarbital .to the; 7
using simu-i man s .demonstrated a similar faster release rate as found in comparing the above data.
Other samples were prepared in which the water-soluble cellulose gum is added subsequent tothe granulation step by blending in the cellulose gum with the dried granules. This method also effects a faster release pattern.
Example IV A stabilized dry form of vitamin A was prepared in accordance with the following formulation to contain 500,000 units of vitamin A per gram.
1 Amount depends on. the potency of the vitamine A source.
1 Equal amounts of butylated hydroxy toluene and butylated hydroxy anisole were added to total 0.05%.
The vitamin A acetate is dissolved in a solvent solution composed of methylene chloride and methyl alcohol containing the antioxidants. This solvent mixture is dispersed on a uniform mixture containing the hydroxy glyceryl ester, cellulose gum, and mannitol. The resulting gel mass is dried in vacuo at 35 C. The dried material is then reduced to a powder.
Storage samples show the following data:
Vitamin A Content,
Time: units per gram Initial 523,000 Eight months at room temperature 491,000
Example V A sample of vitamin B containing 1% of B activity was made in a matrix composed of 20 parts of hydroxyglyceryl ester and 79 parts of mannitol.
An additional sample similar to the above, but also containing 10 parts of cellulose acetate phthalate and 10 parts of polyvinylpyrrolidine in place of part of the mannitol was prepared.
In preparing these samples crystalline vitamin B was dissolved in an organic solvent system composed of methylene chloride and methyl alcohol. The glyceryl ester and mannitol are blended uniformly. In the sample containing polyvinylpyrrolidone, this compound is also mixed with the mannitol mixture. The cellulose acetate phthalate was dissolved in the same solvent system referred to above and the vitamin B incorporated therein.
In each case the solvent phase was dispersed evenly onto the powder mixture and the resulting gel mass was dried in vacuo at 35 C. and subsequently screened into a powder.
Samples stored for six months at room temperature showed no loss in potency in either formulation.
The sample containing the cellulose acetate phthalate, when exposed to an artificial gastric fluid for one hour showed only an 8% release of vitamin B whereas the bulk of the vitamin is released in artificial intestinal fluid within three hours.
In the other sample containing no cellulose acetate phthalate, a gradual release was effected in which 22% was available in acid media after one hour and a gradual release was noted over a 4 hour period in alkaline media.
Example VI A powder sample of ascorbic acid was prepared to contain 3% of hydroxy glyceryl ester and 1% of glucono delta lactone, using a procedure similar to those described in other examples.
6 Samples stored for six months at room temperature and 40 C. showed no darkening or loss of potency.
' Example VII A stable sample of folic acid was prepared containing the hydroxy glyceryl ester, methyl cellulose, mannitol and an antioxidant (butylated hydroxy anisole). The folic acid was converted to its sodium form by dissolving a stoichiometric amount of sodium hydroxide in the alcohol portion of the organic system used to prepare the sample.
The antioxidant was dissolved in the organic phase along with the folic acid. This solution is then dispersed on a uniform blend of the other remaining ingredients. The mass is dried in vacuo at 35 C.
Stability samples show no loss in potency after six months at room temperature.
It should be understood that various changes may be made in the process as herein described without adversely affecting the results attained. Various changes in additives differing from those given in the embodiments of this invention may be made without departing from the spirit and scope thereof. Instead of using a glycerol partial ester of stearic acid, there may be used a glycerol partial ester of palmitic acid, or combinations or mixtures thereof.
What is claimed is:
1. An anhydrous sustained release composition of matter comprising a thixotropic gel containing a hydroxy glycerol ester of a mon'obasic fatty acid of 16 to 18 carbon atoms and having an acid value of 2, and a therapeutic agent dispersed through said gel and releasable therefrom according to a desired pattern.
2. A composition of matter according to claim 1 in which is incorporated an additive selected from the group consisting of carboxy methyl cellulose, methyl cellulose, ethyl cellulose, hydroxy ethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, cellulose acetate phthalate, and mixtures thereof.
3. A composition of matter according to claim 1 in which is incorporated a stabilizer for the therapeutic agent.
4. A composition of matter according to claim 1 in which is incorporated a surfactant.
5. A composition of matter according to claim 1 in which the gel constitutes a matrix in which the therapeutic agent is integrated and by which its physical and chemical stability is increased.
6. A composition of matter according to claim 1 in which the thixotropic gel has been made with at least one anhydrous organic solvent of preselected polarity.
7. A composition of matter according to claim 6 in which the organic solvent is selected from the group consisting of lower alkyl alcohols, trichloroethylene, methylene chloride, acetone, chloroform, petroleum ether and mixtures thereof.
8. A composition of matter comprising a thixotropic gel containing a hydroxy glyceryl ester of stearic acid, an anhydrous organic solvent, and a therapeutic agent dispersed through said gel and releasable therefrom by erosion in the presence of body fluids.
9. A therapeutic composition of matter comprising a thixotropic gel containing a hydroxy glyceryl ester of stearic acid, a volatile anhydrous organic solvent and a therapeutic agent dispersed through said gel and releasable therefrom according to a desired pattern by erosion in the presence of body fluids, said composition being stable and homogeneous and, when dried and screened, formed into dosage units.
10. A therapeutic composition of matter comprising a thixotropic gel containing a hydroxy glyceryl ester of stearic acid, a volatile anhydrous organic solvent and a therapeutic agent admixed with a stabilizing agent therefor dispersed through said gel and releasable therefrom according to a desired pattern by erosion in the presence of body fluids, said composition being stable and homogeneous and, when dried and screened, formed into dosage units.
11. A process that comprises uniformly integrating at least one therapeutically active agent into the hydroxy glyceryl'esterjof a monobasic fattyacid of 16 to'1 8 carbon 1 References Cited in the file of this patent" atoms in an anhydrous system to form a thexotropic gel v UNITED STATES PATENTS Q in which the therapeutic agent is stabilized. g I
12.. A process for preparing a prolonged release ,thera- 2,218,591 Tay1or' Oct. 22;" 1940 peut'rc composition which comprises forming a blend of a 5 2,529,461 Schneide'rwirth i -Nov.- 7, 1950 therapeutic agent, a thixotropic gel and a filler, granulat- 2,895,879 ,BrQwkaw et a1; July' 2 1, 1959 ingthe blend with a solvent mixture of methylene chlQ- 2,921,883 Reese et alf Jam-19, 1960 ride and methyl-alcohol, solidifying the resulting gel mass 2,951,792 7 Swintosky Sept;- 6; 1960 by solventremoval, screening to form granules and tablet- 2,987,445 Levesque June 6', 1961